Role of neoadjuvant therapy in the multimodality treatment of older patients with pancreatic cancer.
A well-defined treatment strategy for elderly patients with resectable pancreatic cancer is lacking. Multiple reports have described highly selected older cancer patients who have successfully undergone pancreatectomy. However, multimodality therapy is essential for long-term survival, and elderly patients are at high risk for not receiving adjuvant therapy postoperatively. We sought to describe the treatment patterns and outcomes of a series of elderly patients with pancreatic cancer who were treated with a multimodality strategy that liberally used neoadjuvant therapy. We retrospectively reviewed treatment plans, short-term outcomes, and overall survival of all patients 70 years old and older, presenting to our institution over a 9-year period, who were treated for potentially resectable or borderline resectable pancreatic cancer. There were 179 (76%) of 236 patients treated with curative intent. Of these patients, 153 (85%) initiated neoadjuvant therapy: 74 (48%) subsequently underwent pancreatectomy and 79 did not due to disease progression (n = 46), insufficient performance status (n = 23), or other reasons (n = 10). Eleven (42%) of 26 patients who underwent surgery first received postoperative therapy. Among patients treated with curative intent, the median overall survival of all patients initiating neoadjuvant therapy (16.6 months [range 2.1 to 142.7 months]) was similar to that of patients undergoing resection primarily (15.1 months [range 5.4 to 100.8 months]), p = 0.53. After pancreatectomy, patients had a 2% in-hospital mortality rate and 91% were discharged home. Eighty-five percent of all patients 70 years old and older, who underwent pancreatectomy for potentially resectable or borderline resectable pancreatic cancer, received multimodality therapy. More than 90% were discharged home. These data demonstrate a potential role for neoadjuvant therapy in selecting elderly patients for surgery, and support further studies to refine individualized treatment protocols for this high-risk population.


Effects of experimental intracerebral hemorrhage on blood flow, capillary permeability, and histochemistry.
Experimental intracerebral hemorrhage has been shown to cause extensive cerebral ischemia. This study was performed to ascertain the time course of these changes and also to examine the type of brain damage that may occur under such circumstances. Halothane anesthesia was induced in rats, and 25 microliter autologous blood was injected into the caudate nucleus; the effects were studied with autoradiographic measurement of local cerebral blood flow and capillary permeability, and also by light microscopy and histochemical techniques. Blood flow returned to normal or to slightly increased levels within the first 3 hours, and ischemic levels of flow were found to persist only to a marginal degree beyond 10 minutes after the lesions were made. Capillary permeability was maximum during the first 30 minutes after the hemorrhage and diminished with time. Structural evidence of ischemic damage was localized to the cortex overlying the hemorrhage, but was not seen in the caudate nucleus. Nevertheless, histochemical investigation did reveal an area of disturbed enzyme function in the striatum. This finding of biochemical disturbance without structural evidence of ischemic damage reveals that there is an area around the hematoma that, although demonstrating disturbed function, does not show structural damage, and the milieu of this partially injured brain may be implicated in the delayed development of the ischemic brain damage that follows intracerebral hemorrhage in man.


Sound levels in classrooms and effects on self-reported mood among school children.
The principle of this field study is an investigation of recorded sound levels in 24 classrooms and relations between sound level measures and aspects of children's rated annoyance, task orientation, and inattentiveness. The background sound-exposure levels were distributed within the interval of 33-42 dB(A)eq and the activity sound level exposure ranged between 47-68 dB(A)eq. The recorded levels must be considered as high for work environments where steady concentration and undisturbed communication is essential. Results do not support the hypothesis that lower background-sound level and fewer students per class would improve the sound environment by generating a lower activity noise or the hypothesis that higher sound levels should increase annoyance and inattentiveness as well as deteriorate task orientation ratings.


Comorbidity of Ocular and Facial Demodicosis.
To determine the association between ocular and facial demodicosis, and the effect of facial treatment on ocular demodicosis. Prospective clinical cohort study. Ocular demodicosis outpatients from a tertiary medical center were enrolled from April to December 2020. The diagnosis was based on epilation of 4 eyelashes from each upper eyelid. High ocular Demodex load (ODL) was defined as ≥8 mites per eye. Facial infestation was assessed by direct microscopic examination, with facial Demodex overgrowth (FDO) defined as a density >5 mites/cm2. All patients were prescribed 3 months of ocular treatment, and FDO patients received dermatologic treatment. Eighty-nine patients were enrolled. Among those that completed the treatment course, 39 presented high ODL. Lower cylindrical sleeve counts were found in low ODL patients (low ODL vs high ODL: 8 vs 14, P = .009). FDO was less prevalent in this group (49% vs 77%, P = .012). The Ocular Surface Disease Index score decreased in patients without FDO (20.0 ± 17.1 to 14.0 ± 16.6, P = .027) after 3 months of topical tea tree oil treatment. Topical ivermectin treatment on the facial skin provided a higher ocular Demodex eradication rate in FDO patients (76% vs 16%, P < .001). Concurrence of ocular and facial demodicosis is common, especially in cases of severe ocular demodicosis. Although ocular treatment alone is effective for patients with ocular demodicosis only, cotreatment with topical ivermectin on the facial skin enhances ocular Demodex eradication in patients with comorbid facial Demodex overgrowth.


Vitamins and sport.
In a double blind test on 40 men and women high performance fencers the influence of a multivitamin-electrolyte-preparation on reaction time, hit-frequency and neuromuscular irritability was determined. Evidence of B1, B2 and B6-deficiencies up to 70% were found. After application of the preparation an increase of performance of 3% could be observed. The tests were carried out by means of coenzymatic activation of the respective vitamins in the haemolysate of erythrocytes. The results are explained by the role of the vitamins in the human organism and by the special conditions under which endurance athletes have to perform: high turn-over rate of the energy metabolism, an increase of the body core temperature and thus increased sweat loss, factors leading to deficiencies of the water soluble B-vitamins.


Monocytes harbour replication-competent, non-latent HIV-1 in patients on highly active antiretroviral therapy.
To determine whether HIV-1 can be recovered from blood monocytes as well as resting, memory CD4 T lymphocytes of patients on highly active antiretroviral therapy (HAART) with undetectable plasma viraemia and whether infection is active or latent. Five patients with plasma HIV-1-RNA levels of less than 500 copies/ml for at least 3 months and less than 50 copies/ml at the time of sampling were initially selected, followed by an additional five patients with viral loads of less than 50 copies/ml for 3 months or more. Monocytes were isolated from blood by plastic adherence, then further purified by a second adherence step or CD3 depletion before co-culture with CD8-depleted donor peripheral blood mononuclear cells. Virus isolates were examined for mutations conferring resistance to reverse transcriptase or protease inhibitors and for genotype. The highly purified monocytes were also analysed for the presence of proviral and unintegrated viral DNA and multiply spliced (MS) viral mRNA by polymerase chain reaction. Virus was recovered from monocytes of five patients. Sequencing of the recovered viruses did not reveal multiple drug resistance, and was consistent with a non-syncytium-inducing/CCR5 phenotype. Proviral DNA was detectable in monocytes from all subjects, and unintegrated HIV-1 DNA and MS RNA was found in four out of five populations examined. Recovery of replication-competent virus from some HAART patients indicates that monocytes can also harbour HIV-1. Detection of circular, viral DNA and spliced RNA, albeit at very low levels, in these cells suggests that their infection is recent and transcriptionally active rather than latent.


[Clinical and histological characteristics of ictal onset zone in cases of intractable epilepsy associated with dysembryoplastic neuroepithelial tumor].
Although the epileptogenic location of dysembryoplastic neuroepithelial tumors (DNTs) is controversial, it has recently been thought to be located within cortical dysplasia (CD) due to its frequent association with CD. Among the 84 resection surgeries for intractable epilepsy performed in our institution between January 2003 and April 2010, three patients had epileptogenic DNTs. In two cases, chronic subdural electrocorticography (ECoG) was performed, and the ictal onset zone was revealed to be in the cortex around the DNT. The ictal onset zone was resected along with the DNT, and good seizure outcome was achieved. Although histological examination of the ictal onset zone revealed mild gliosis, coexistence of CD was not noted. In the third case, the DNT was located in the left lateral temporal lobe and the intraoperative ECoG revealed frequent paroxysmal activity in the medial temporal lobe. Resection of the lateral temporal lobe involving the tumor did not result in good seizure control. The optimal surgical treatment of DNT is controversial. Some authors consider lesionectomy to be sufficient for good seizure control, whereas others advocate that additional resection of the epileptogenic zone beside the tumor improves outcome. Because the epileptogenic location of DNT varies among cases, it is important to identify its location by preoperative multimodal examinations, including chronic subdural ECoG recordings.


Neutrophil hyper-responsiveness in periodontitis.
Peripheral neutrophil hyper-responsiveness in chronic periodontitis leads to excessive reactive oxygen species (ROS) production. We aimed to determine whether neutrophil hyper-responsiveness was constitutive or reactive, and to discover the effect of non-surgical therapy. Peripheral blood neutrophils from patients (n = 19), before and 3 months after therapy, and matched control individuals were Fc gamma-receptor-stimulated with/without priming with P. gingivalis and F. nucleatum. Total and extracellular ROS were determined by luminol/isoluminol chemiluminescence. The high total ROS generation of patients' neutrophils compared with that of control individuals (P = 0.016) continued at a reduced level post-therapy (P = 0.059). Reduced activity post-therapy was also seen with priming. Unstimulated total ROS levels did not differ between patients and control individuals before or after therapy. However, the high unstimulated, extracellular ROS production by patients' neutrophils compared with control individuals (P < 0.05) continued post-therapy and was unaffected by priming. Therapy reduced Fc gamma-receptor-stimulated total ROS production, but not unstimulated extracellular radical release, suggesting that constitutive and reactive mechanisms underlie neutrophil hyper-responsiveness.


EMG pattern recognition based on artificial intelligence techniques.
This paper presents an electromyographic (EMG) pattern recognition method to identify motion commands for the control of a prosthetic arm by evidence accumulation based on artificial intelligence with multiple parameters. The integral absolute value, variance, autoregressive (AR) model coefficients, linear cepstrum coefficients, and adaptive cepstrum vector are extracted as feature parameters from several time segments of EMG signals. Pattern recognition is carried out through the evidence accumulation procedure using the distances measured with reference parameters. A fuzzy mapping function is designed to transform the distances for the application of the evidence accumulation method. Results are presented to support the feasibility of the suggested approach for EMG pattern recognition.


Views and perceptions of Australian physiotherapists and physiotherapy students about the potential implementation of physiotherapist prescribing in Australia: a survey protocol.
Non-medical prescribing (NMP) is acknowledged as an expanding area of clinical practice across the world. The physiotherapy profession is currently investigating the introduction of physiotherapist prescribing in Australia, with the case for reform centred around meeting the healthcare needs of the current and future Australian population. Conflict within a profession has been identified as a barrier to implementation of new clinical innovations. An online survey has been developed with the aim to collect and synthesise the views and perceptions of Australian physiotherapists and physiotherapy students about the potential use of NMP by physiotherapists in Australia. A cross-sectional descriptive survey design, using a pre-tested online questionnaire, including quantitative and qualitative components, will be utilised to explore the views and perceptions of Australian physiotherapists and physiotherapy students regarding NMP by physiotherapists in Australia. Quantitative data will be analysed descriptively and regression analysis will be utilised to identify associations between the specific question outcomes and demographic data. A thematic analytical approach will be utilised to synthesise qualitative data from open-questions. The results from this survey will serve to inform decision-makers about the current views of the Australian physiotherapy profession with regards to the potential implementation of physiotherapist prescribing in Australia. Data will be used in conjunction with cost-benefit analyses, risk analysis as well as assessment of the health-requirements and consultation with key stakeholders including the Australian health consumer when contemplating change.


HFpEF: New biomarkers and their diagnostic and prognostic value.
Heart failure characterized by preserved ejection fraction (HFpEF) poses a substantial challenge to healthcare systems worldwide and the diagnostic algorithms used currently mirror those utilized for reduced Ejection Fraction (HFrEF). This literature review aims to explore the diagnostic and prognostic credibility of numerous emerging biomarkers associated with HFpEF. We conducted a thorough analysis of the available medical literature and selected the biomarkers which yielded the maximum amount of published information. After reviewing the current literature we conclude that there are no biomarkers at present which are superior to natriuretic peptides in terms of diagnosis and prognosis of HFpEF. However biomarkers like Suppression of tumorigenicity2, Galectin3 and microRNAs are promising and can be researched further for future use. Although newer individual biomarkers may not be useful in diagnosing and prognosis of HFpEF, we believe that a specific biomarker profile may be identified in each phenotype,which can be used in future.


Efficient gene transfer in C.elegans: extrachromosomal maintenance and integration of transforming sequences.
We describe a dominant behavioral marker, rol-6(su-1006), and an efficient microinjection procedure which facilitate the recovery of Caenorhabditis elegans transformants. We use these tools to study the mechanism of C.elegans DNA transformation. By injecting mixtures of genetically marked DNA molecules, we show that large extrachromosomal arrays assemble directly from the injected molecules and that homologous recombination drives array assembly. Appropriately placed double-strand breaks stimulated homologous recombination during array formation. Our data indicate that the size of the assembled transgenic structures determines whether or not they will be maintained extrachromosomally or lost. We show that low copy number extrachromosomal transformation can be achieved by adjusting the relative concentration of DNA molecules in the injection mixture. Integration of the injected DNA, though relatively rare, was reproducibly achieved when single-stranded oligonucleotide was co-injected with the double-stranded DNA.


Overweight is risking fate.
Obesity is the result of ancient evolutionary survival mechanisms in a modern environment of affluence. When pressures from this environment generate a long-term or chronic hypothalamic arousal, neuroendocrine-endocrine and autonomic nervous systems are activated, leading to disease-generating 'risk factors' including the metabolic syndrome, with visceral fat accumulation as a conveniently observable marker. The susceptibility to develop these co-morbidities is probably dependent on a functional defect of the inhibitory feedback control of the hypothalamus-pituitary-adrenal axis by central glucocorticoid receptors, often based on a prevalent polymorphism of the gene locus for this receptor. This means that moderate ('peripheral') obesity is a fairly innocent condition while, when hypothalamic arousal is added, as indicated by the internalization of excess body fat ('central' obesity), a highly malignant condition develops in genetically susceptible individuals. Obesity research would benefit from a distinction between these two types of condition.


Metabolism and excretion of kakkalide and its metabolites in rat urine, bile, and feces as determined by HPLC/UV and LC/MS/MS.
This study investigated the metabolic fate of kakkalide (irisolidone 7-xylosylglucoside), a major isoflavone found in extracts of Pueraria lobata flowers, and in rat urine, bile, and feces. Using HPLC/UV or LC/MS/MS methods, seven metabolites, tectorigenin-7-O-glucuronide, tectorigenin-7-O-sulfate, tectorigenin-4'-O-sulfate, 6-OH biochanin A-glucuronide, irisolidone-7-O-glucuronide, tectorigenin, and irisolidone were identified in rat urine after oral administration of kakkalide. Furthermore, irisolidone-7-O-glucuronide was found in bile, and irisolidone and kakkalide were found in feces. An HPLC/UV method for simultaneous quantification of all the metabolites and kakkalide in urine, bile, and feces was developed using daidzein or apigenin as the internal standard. Over a 72-h period, 13.2 ± 2.8 % of the kakkalide was excreted as seven metabolites in urine. Over the same time period, irisolidone-7-O-glucuronide excretion in bile accounted for 3.8 ± 1.1 % of the dose, while kakkalide and irisolidone excretion in feces accounted for 2.1 ± 0.7 % and 0.7 ± 0.1 % of the dose, respectively. The results indicate that urine is the primary route of kakkalide elimination in vivo and that extensive metabolism may be one of the reasons for the low bioavailability of kakkalide.


Failure of the vaccination campaign against A(H1N1) influenza in pregnant women in France: results from a national survey.
Pregnant women were a priority group for vaccination during the 2009 A(H1N1) influenza pandemic. In France, vaccination was organized in ad hoc centers. Women received vouchers by mail and were given a non-adjuvanted vaccine. Our objective was to assess the national vaccination rate among pregnant women and to determine the association of vaccination with maternal characteristics, prenatal care, and pregnancy-related health behaviors. Data came from a national representative sample of women who gave birth in March 2010 (N=13 453) and were interviewed in the hospital before discharge; they were in the second trimester of pregnancy during the vaccination campaign. Associations between vaccination and socio-demographic and medical characteristics, region of residence, care providers, and preventive behaviors were assessed with bivariable analyses and logistic regression models. Vaccine coverage was 29.3% (95% CI: 28.6-30.1). The main reason for not being vaccinated was that women did not want this immunization (91%). In adjusted analyses, vaccination was more frequent in women who were older, employed, born in France, with a parity of 1 or 2 and specific favourable health behaviors. The adjusted odds ratio for women with a postgraduate educational level was 4.1 (95% CI: 3.5-4.8) compared to those who did not complete high school. Women with additional risk factors for complications from A(H1N1) infection had a vaccination rate similar to that of other women. The vaccination campaign resulted in poor vaccination coverage, strong social inequalities, and no special protection for pregnant women at the highest risk of complications. These findings provide essential information for the organization of future vaccination campaigns.


Development of a tool within the electronic medical record to facilitate medication reconciliation after hospital discharge.
Serious medication errors occur commonly in the period after hospital discharge. Medication reconciliation in the postdischarge ambulatory setting may be one way to reduce the frequency of these errors. The authors describe the design and implementation of a novel tool built into an ambulatory electronic medical record (EMR) to facilitate postdischarge medication reconciliation. The tool compares the preadmission medication list within the ambulatory EMR to the hospital discharge medication list, highlights all changes, and allows the EMR medication list to be easily updated. As might be expected for a novel tool intended for use in a minority of visits, use of the tool was low at first: 20% of applicable patient visits within 30 days of discharge. Clinician outreach, education, and a pop-up reminder succeeded in increasing use to 41% of applicable visits. Review of feedback identified several usability issues that will inform subsequent versions of the tool and provide generalizable lessons for how best to design medication reconciliation tools for this setting.


Medicinal plant biotechnology.
Biotechnology is described as methodology to enhance the formation and accumulation of desirable natural products and possible product modification in medicinal plants. Micropropagation, cell and hairy root culture as well as gene technology are being highlighted.


Dysregulated NF-κB pathway in peripheral mononuclear cells of Alzheimer's disease patients.
Diagnosis and therapeutic strategies in Alzheimer's disease (AD) might greatly benefit of the present multidisciplinary approach for studying the molecular pathogenesis of the disorder. Gene expression profile at peripheral level could be a promising tool for pathogenic studies as well as for early diagnosis of AD. A dysregulated inflammatory response, as well as other systemic disorders, have been described in AD. Therefore, we investigated the expression, at peripheral level, of a number of genes involved in the inflammatory, oxidative stress and proliferative response of a well defined, small cohort of sporadic AD patients. Firstly, the mRNA expression of inflammatory, stress and proliferation/ differentiation genes were evaluated, using SuperArray, in mitogen-stimulated peripheral blood mononuclear cells (PBMC) from a group of 12 well-characterized, sporadic AD patients with various levels of dementia, by comparison with aged-matched controls. Real-time RT-PCR confirmed the trend of alteration in 16 genes out of the 36 supposed to be dysregulated in AD patients, by the preliminary screening. The expression level of the NFKB1(p105/50Kd) gene was significantly higher in AD with respect to adult age-matched controls (AA) and was related to the Mini-Mental State Examination (MMSE) score of the same patients. In addition, the expression of various NF-κB target genes and of both NF-κBp50 and NF-κBp65 DNA-binding activity were increased in PBMC from AD patients in comparison with those from AA. Our results suggest that NF-κB activation at peripheral blood cell level could be a potential new hallmark of AD progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-κB inhibitors in AD.


Disinfection of ocular cells and tissues by atmospheric-pressure cold plasma.
Low temperature plasmas have been proposed in medicine as agents for tissue disinfection and have received increasing attention due to the frequency of bacterial resistance to antibiotics. This study explored whether atmospheric-pressure cold plasma (APCP) generated by a new portable device that ionizes a flow of helium gas can inactivate ocular pathogens without causing significant tissue damage. We tested the APCP effects on cultured Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Candida albicans, Aspergillus fumigatus and Herpes simplex virus-1, ocular cells (conjunctival fibroblasts and keratocytes) and ex-vivo corneas. Exposure to APCP for 0.5 to 5 minutes significantly reduced microbial viability (colony-forming units) but not human cell viability (MTT assay, FACS and Tunel analysis) or the number of HSV-1 plaque-forming units. Increased levels of intracellular reactive oxygen species (ROS) in exposed microorganisms and cells were found using a FACS-activated 2',7'-dichlorofluorescein diacetate probe. Immunoassays demonstrated no induction of thymine dimers in cell cultures and corneal tissues. A transient increased expression of 8-OHdG, genes and proteins related to oxidative stress (OGG1, GPX, NFE2L2), was determined in ocular cells and corneas by HPLC, qRT-PCR and Western blot analysis. A short application of APCP appears to be an efficient and rapid ocular disinfectant for bacteria and fungi without significant damage on ocular cells and tissues, although the treatment of conjunctival fibroblasts and keratocytes caused a time-restricted generation of intracellular ROS and oxidative stress-related responses.


Mucin dynamics in the chick small intestine are altered by starvation.
The absorptive surface of the small intestine is covered by a layer of mucus secreted by goblet cells. The secreted mucins and thickness of the adherent layer influence nutrient digestion and absorption processes as well as the functionality of the mucosa. In this study, methods for the analysis of mucin synthesis and dynamics in the chick small intestine are described. A fragment of chicken mucin cDNA was isolated and characterized; this fraction had 60% homology to human mucin MUC-5AC. The thickness of the mucus adherent layer and the relative amounts of mucin glycoprotein and mRNA were also examined in the small intestines of control and starved chicks. Relative amounts of intestinal mucin mRNA and protein increased in the duodenum and jejunum of starved chicks, and mucus adherent layer thickness decreased throughout the small intestine. In starved chicks, higher mRNA expression and protein concentrations with lower amounts of adherent mucus may be related to a higher rate of degradation of the mucus layer, a lower rate of mucus secretion, or an altered rate of mucin turnover. It thus appears that starvation alters mucus dynamics in the small intestine, and this may affect intestinal digestive function and defense.


[Exposure to radon-222 of inhabitants of buildings in Olsztyn].
The concentrations of radon-222 in the air of some buildings in Olsztyn were measured. The main source of radon in buildings is in general the ground under building and the materials used for building structure. In this work the results of radon-222 concentration measurements in the air of some buildings constructed before the 1939 year, in the buildings constructed after 1945 year with the traditional use of the bricks and in the buildings constructed with the use of great prefabricated plates are presented. The relations between radon-222 concentrations in the basements and in the first floor flats situated above the basement were evaluated. Based on the mean radon concentrations in the air of the various types of buildings investigated the effective doses for the inhabitants of each type of buildings were estimated.


[Relation between changes in the breathing of patients with aneurysmal and stenotic lesions of the major cerebral vessels and the side of the lesion].
In patients with aneurysmal and stenosing injuries to the main vessels of the brain, there are significant differences in the duration of respiration arrests, respiration rate, systole frequency, basic metabolism, thermoregulation reflexes depending on the lateralization of vascular injury. Asymmetry manifested most distinctly in the pathology of the anterior cerebral artery. In women, functional asymmetry was pronounced to a greater extent than in men. Lateralization of the neurological symptomatology is also of importance for the line of ventilatory changes.


Cancer mortality disparities among New York City's Upper Manhattan neighborhoods.
The East Harlem (EH), Central Harlem (CH), and Upper East Side (UES) neighborhoods of New York City are geographically contiguous to tertiary medical care, but are characterized by cancer mortality rate disparities. This ecological study aims to disentangle the effects of race and neighborhood on cancer deaths. Mortality-to-incidence ratios were determined using neighborhood-specific data from the New York State Cancer Registry and Vital Records Office (2007-2011). Ecological data on modifiable cancer risk factors from the New York City Community Health Survey (2002-2006) were stratified by sex, age group, race/ethnicity, and neighborhood and modeled against stratified mortality rates to disentangle race/ethnicity and neighborhood using logistic regression. Significant gaps in mortality rates were observed between the UES and both CH and EH across all cancers, favoring UES. Mortality-to-incidence ratios of both CH and EH were similarly elevated in the range of 0.41-0.44 compared with UES (0.26-0.30). After covariate and multivariable adjustment, black race (odds ratio=1.68; 95% confidence interval: 1.46-1.93) and EH residence (odds ratio=1.20; 95% confidence interval: 1.07-1.35) remained significant risk factors in all cancers' combined mortality. Mortality disparities remain among EH, CH, and UES neighborhoods. Both neighborhood and race are significantly associated with cancer mortality, independent of each other. Multivariable adjusted models that include Community Health Survey risk factors show that this mortality gap may be avoidable through community-based public health interventions.


Allotypy of rabbit serum proteins. II. Relationships between various allotypes: their common antigenic specificity, their distribution in a sample population; genetic implications.
The relationships between six of the seven allotypes or families of allotypes (a, b, c, d, f, g) described in the preceding paper, have been studied from the standpoints of (1) their antigenic specificities, (2) their mutual influence on the limitation of their respective frequencies, and (3) their genetic control. Although the six different allotypes (or families) react quite differently with the rabbit antisera, at least five of them react identically with a guinea pig antiserum. Therefore, a large portion of the antigenic specificity of these allotypes, distinct from their allotypic specificity, is uniform in all the individuals of the rabbit species and is termed for this reason "isotypic specificity." In the early period of the rabbit's life, allotypes may be found in the serum, which are not determined by the genotype of the individual, but are directly transmitted by the mother. The allotypes of the antigenic species of globulin studied in this paper, which were synthesized by the young animal, did not appear in its serum before a certain period of time. Allelic relationships between the genes which control allotypes were indicated by, (1) the absence of certain kinds of groupings of the allotypes, which limits the number of allotypic formulas in the population sample studied, (2) dosage effects, the concentration of certain allotypes (drawn from the penetration of the zones in gel tubes) being smaller in supposed heterozygotes than in supposed homozygotes, (3) the results of the analysis of the sera of a number of rabbits and of their parents. Eight of the different antigenic substances studied in this paper (allotype e excluded) appear to be allotypic forms of what would have been considered to be a uniform protein antigen. They may be classified as follows: a first group which contains two allotypes b and d and a family of two allotypes c and c' apparently controlled by three allelic genes b c d, c and c' being controlled by the same gene; a second group which contains two allotypes a and f and a family g, g' apparently controlled by three allelic genes a f g. There are reasons to believe that this list is not complete, especially in the b c d group.


A core set of venom proteins is released by entomopathogenic nematodes in the genus Steinernema.
Parasitic helminths release molecular effectors into their hosts and these effectors can directly damage host tissue and modulate host immunity. Excreted/secreted proteins (ESPs) are one category of parasite molecular effectors that are critical to their success within the host. However, most studies of nematode ESPs rely on in vitro stimulation or culture conditions to collect the ESPs, operating under the assumption that in vitro conditions mimic actual in vivo infection. This assumption is rarely if ever validated. Entomopathogenic nematodes (EPNs) are lethal parasites of insects that produce and release toxins into their insect hosts and are a powerful model parasite system. We compared transcriptional profiles of individual Steinernema feltiae nematodes at different time points of activation under in vitro and in vivo conditions and found that some but not all time points during in vitro parasite activation have similar transcriptional profiles with nematodes from in vivo infections. These findings highlight the importance of experimental validation of ESP collection conditions. Additionally, we found that a suite of genes in the neuropeptide pathway were downregulated as nematodes activated and infection progressed in vivo, suggesting that these genes are involved in host-seeking behavior and are less important during active infection. We then characterized the ESPs of activated S. feltiae infective juveniles (IJs) using mass spectrometry and identified 266 proteins that are released by these nematodes. In comparing these ESPs with those previously identified in activated S. carpocapsae IJs, we identified a core set of 52 proteins that are conserved and present in the ESPs of activated IJs of both species. These core venom proteins include both tissue-damaging and immune-modulating proteins, suggesting that the ESPs of these parasites include both a core set of effectors as well as a specialized set, more adapted to the particular hosts they infect.


IL8 and serum soluble TRAIL levels following anti-VEGF monoclonal antibody treatment in patients with metastatic colon cancer.
Colorectal cancer is the third most common human cancer and the third leading cause of cancer related death. BevacizumAb is a humanized monoclonal antibody developed against vascular endothelial growth factor (VEGF) for the treatment of metastatic cancers. Our goal was to evaluate the possibility of using serum sTRAIL and IL8 as markers of treatment efficacy and prognosis in patients with metastatic colon cancer. The study was conducted in Denizli between November 10, 2009 and September 20, 2010. 25 patients (6 female, 19 male) with metastatic colon cancer whose mean age was 58.7 years, were selected and included in the study. All patients received therapy with BevacizumAb. All patients were followed in the Oncology Clinic of Denizli State Hospital and were evaluated by clinical status, sTRAIL and IL8 levels were measured by ELISA in the sera of 25 BevacizumAb treated metastatic colon cancer patients and 20 healthy age-gender matched controls. Measurements were taken before and after treatment. The serum sTRAIL concentrations in patients before therapy were similar to those of healthy age-gender matched controls, namely 1.23 +/- 0.06 ng/mL and 1.21 +/- 0.04 ng/mL, respectively. After BevacizumAb treatment, sTRAIL ratios were increased significantly in 11 of 25 patients. 14 patients showed progressive disease with median overall survival of only 8.1 +/- 0.4 months. These 14 patients were the same ones who showed no increase in sTRAIL levels after BevacizumAb treatment. We explored evidence for a correlation between sTRAIL levels and overall survival rates and observed that elevated sTRAIL levels after the BevacizumAb treatment were significantly associated with increased median overall survival up to 22.6 months. Serum IL8 levels were decreased in all patients who received BevacizumAb therapy. In BevacizumAb therapy, serum IL8 levels were decreased in all patients, and thus, changes in such levels were not correlated with disease outcome. Our data suggest measurement of changes in sTRAIL following BevacizumAb treatment may have prognostic value in metastatic colon cancer patients.


Protein kinase C-theta is required for efficient positive selection.
Protein kinase C-theta (PKCtheta) is critical for TCR-initiated signaling in mature T cells, but initial reports found no requirement for PKCtheta in thymocyte development. Thymocytes and peripheral T cells utilize many of the same signaling components and, given the significant role of PKCtheta in peripheral T cells, it was surprising that it was not involved at all in TCR signaling in thymocytes. We decided to re-evaluate the role of PKCtheta in thymocyte development using the well-characterized class II-restricted n3.L2 TCR-transgenic TCR model. Analysis of n3.L2 PKCtheta(-/-) mice revealed a defect in thymocyte-positive selection, resulting in a 50% reduction in the generation of n3.L2 CD4 single-positive thymocytes and n3.L2 CD4 mature T cells. Competition between n3.L2 WT and n3.L2 PKCtheta(-/-) thymocytes in bone marrow chimeras revealed a more dramatic defect, with a >80% reduction in generation of n3.L2 CD4 single-positive thymocytes derived from PKCtheta(-/-) mice. Inefficient positive selection of n3.L2 PKCtheta(-/-) CD4 single-positive cells resulted from "weaker" signaling through the TCR and correlated with diminished ERK activation. The defect in positive selection was not complete in the PKCtheta(-/-) mice, most likely accounted for by compensation by other PKC isoforms not evident in peripheral cells. Similar decreased positive selection of both CD4 and CD8 single-positive thymocytes was also seen in nontransgenic PKCtheta(-/-) mice. These findings now place PKCtheta as a key signaling molecule in the positive selection of thymocytes as well as in the activation of mature T cells.


Weather effects on avian breeding performance and implications of climate change.
The influence of recent climate change on the world's biota has manifested broadly, resulting in latitudinal range shifts, advancing dates of arrival of migrants and onset of breeding, and altered community relationships. Climate change elevates conservation concerns worldwide because it will likely exacerbate a broad range of identified threats to animal populations. In the past few decades, grassland birds have declined faster than other North American avifauna, largely due to habitat threats such as the intensification of agriculture. We examine the effects of local climatic variations on the breeding performance of a bird endemic to the shortgrass prairie, the Lark Bunting (Calamospiza melanocorys) and discuss the implications of our findings relative to future climate predictions. Clutch size, nest survival, and productivity all positively covaried with seasonal precipitation; yet relatively intense daily precipitation events temporarily depressed daily survival of nests. Nest survival was positively related to average temperatures during the breeding season. Declining summer precipitation may reduce the likelihood that Lark Buntings can maintain stable breeding populations in eastern Colorado although average temperature increases of up to 3 degrees C (within the range of this study) may ameliorate declines in survival expected with drier conditions. Historic climate variability in the Great Plains selects for a degree of vagility and opportunism rather than strong site fidelity and specific adaptation to local environments. These traits may lead to northerly shifts in distribution if climatic and habitat conditions become less favorable in the drying southern regions of the Great Plains. Distributional shifts in Lark Buntings could be constrained by future changes in land use, agricultural practices, or vegetative communities that result in further loss of shortgrass prairie habitats.


Uncommon hepatic tumors: iconographic essay - Part 2.
In cases where typical aspects are shown, the diagnosis of most frequent hepatic lesions can be made with some safety by means of several imaging methods; on the other hand, uncommon lesions generally represent a diagnostic challenge for the radiologist. In the present second part of the study, the authors describe four rare hepatic lesions, as follows: primary hepatic lymphoma, myofibroblastic tumor, primary hepatic neuroendocrine tumor and desmoplastic small round cell tumor, approaching their main characteristics and imaging findings with emphasis on computed tomography and magnetic resonance imaging.


Sex increases the probability of evolutionary rescue in the presence of a competitor.
The explanation for the continued existence of sex, despite its many costs, remains one of the major challenges of evolutionary biology. Previous experimental studies have demonstrated that sex increases the rate of adaptation in novel environments relative to asexual reproduction. Whereas these studies have investigated the impact of sex on adaptation to stressful abiotic environments, the potential for biotic interactions to influence this advantage of sex has been largely ignored. Species rarely exist in isolation in natural conditions, so the impact of sex on adaptation to a stressful abiotic environment may be altered by the interactions between coexisting species. To investigate the interplay of sex and competition on adaptation to deteriorating conditions, we allowed populations of the unicellular alga (Chlamydomonas reinhardtii) to evolve in an environment to which they were initially poorly adapted. We manipulated both their mode of reproduction and the presence of a competitor, and monitored population size and proportion of evolutionary rescue events for each mode of reproduction. The results indicate that sex may be the beneficial strategy in the presence of the competitor. Sexual populations had highest probability of evolutionary rescue irrespective of the presence of the competitor. The overall advantage of sex was also manifested through higher level of adaptedness of survived sexual populations relative to asexual populations. Since competitive interactions are commonplace in nature, one of the explanations for the maintenance of sex by natural selection may be the increased rate of adaptation of sexual populations both in the presence and absence of competitors.


Cutting edge: Cytosolic bacterial DNA activates the inflammasome via Aim2.
Pathogens are detected by pattern recognition receptors that, upon activation, orchestrate an appropriate immune response. The TLRs and the nucleotide-binding oligomerization domain-like receptors (NLRs) are prototypic pattern recognition receptors that detect extracellular and cytosolic pathogens, respectively. Listeria monocytogenes has both extracellular and cytosolic phases and is detected in the cytosol by members of the NLR family. These include two NLR members, NLRC4 and NLRP3, that, upon detection of cytosolic L. monocytogenes, induce the assembly of the inflammasome. Inflammasomes serve as platforms for the activation of the protease caspase 1, which mediates the processing and secretion of pro-IL-1beta and pro-IL-18. We previously provided evidence that L. monocytogenes is also detected by a third inflammasome. We now use biochemical and genetic approaches to demonstrate that the third detector senses bacterial DNA and identify it as Aim2, a receptor that has previously been shown to detect viral DNA.


Advancing Nursing Practice: Management of Neuropathic Pain With Capsaicin 8% Without Physician Supervision.
The purpose of this study was to examine the management of patient's neuropathic pain with capsaicin 8% in a nurse-led clinic when administered by 1 registered advanced nurse practitioner without physician supervision. A longitudinal, single-group, descriptive research design was used to assess pain scores and quality of life 3 times over 3 months after treatment. Patients with a diagnosis of neuropathic pain were assessed and treated with capsaicin 8% by 1 advanced nurse practitioner with prescriptive authority in a nurse-led clinic. Pain scores were collected at baseline, and self-assessed pain, activity level, and quality of life were assessed at 1 week, 4 weeks, and 3 months after treatment. Twenty-four patients were recruited, and data were analyzed using Friedman's test. In post hoc analysis, Wilcoxon signed-rank test was used with Bonferroni correction. Pain scores differed from pretreatment to posttreatment at each of the 3 time points, at rest (χ3 = 20.54, P = .001) and on movement (χ3 = 23.644, P = .001), and remained significant after Bonferroni correction. Overall, 62.5% (n = 15) of patients achieved at least a 30% reduction in self-reported pain at rest from pretreatment to 3 months, and 54% (n = 13) achieved the same reduction in pain on movement. Most improvements in patient's quality of life occurred between 1 and 4 weeks. Patient satisfaction was high, with 83% stating that they would be happy to have the treatment repeated. Single-dose capsaicin 8% decreased neuropathic pain after being administered in an outpatient setting by an experienced registered advanced nurse practitioner. Further multicenter research led by advanced nurse practitioners is needed to support high-quality, safe treatment of neuropathic pain with high-concentration capsaicin in nurse-led chronic pain clinics.


Effect of age and dietary restriction on the expression of alpha 2u-globulin.
The effect of aging on the expression of alpha 2u-globulin was studied in liver tissue from 6-30-month-old male Fischer F344 rats. The synthesis of alpha 2u-globulin by suspensions of isolated hepatocytes decreased 90% between 6 and 22 months of age. The levels of alpha 2u-globulin mRNA and the transcription of alpha 2u-globulin genes by isolated liver nuclei decreased 80-85% between 5 and 24 months of age. Because alpha 2u-globulin has been suggested to be a "senescence marker protein," the expression of alpha 2u-globulin was measured in rats fed a diet restricted in calories. This dietary restriction procedure has been shown to increase significantly the longevity of rodents. The expression of alpha 2u-globulin was compared in liver tissue from 18-month-old rats fed ad libitum and a restricted diet (40% restriction of total calories). The synthesis, mRNA levels, and transcription of alpha 2u-globulin were 1.8-3-fold higher for liver tissue from restricted rats compared to liver tissue from rats fed ad libitum. Therefore, dietary restriction alters the age-related change in the expression of alpha 2u-globulin. Our results demonstrate that the changes in alpha 2u-globulin expression that arise during aging or dietary restriction are regulated at the level of transcription.


Individual-based simulation of the spatial and temporal dynamics of macroinvertebrate functional groups provides insights into benthic community assembly mechanisms.
The complexity and scales of the processes that shape communities of marine benthic macroinvertebrates has limited our understanding of their assembly mechanisms and the potential to make projections of their spatial and temporal dynamics. Individual-based models can shed light on community assembly mechanisms, by allowing observed spatiotemporal patterns to emerge from first principles about the modeled organisms. Previous work in the Rance estuary (Brittany, France) revealed the principal functional components of its benthic macroinvertebrate communities and derived a set of functional relationships between them. These elements were combined here for the development of a dynamic and spatially explicit model that operates at two spatial scales. At the fine scale, modeling each individual's life cycle allowed the representation of recruitment, inter- and intra-group competition, biogenic habitat modification and predation mortality. Larval dispersal and environmental filtering due to the tidal characteristics of the Rance estuary were represented at the coarse scale. The two scales were dynamically linked and the model was parameterized on the basis of theoretical expectations and expert knowledge. The model was able to reproduce some patterns of α- and β-diversity that were observed in the Rance estuary in 1995. Model analysis demonstrated the role of local and regional processes, particularly early post-settlement mortality and spatially restricted dispersal, in shaping marine benthos. It also indicated biogenic habitat modification as a promising area for future research. The combination of this mechanism with different substrate types, along with the representation of physical disturbances and more trophic categories, could increase the model's realism. The precise parameterization and validation of the model is expected to extend its scope from the exploration of community assembly mechanisms to the formulation of predictions about the responses of community structure and functioning to environmental change.


An updated history of the Teratology Society.
The 49-year history of the Teratology Society is reviewed. An abbreviated history is outlined in table form, with listings of the Warkany Lectures, the Continuing Education Courses, and officers of the society. The original article was updated to include the years 2000 to 2010. A year-by-year description of the events is given, including the scientific and social content of the annual meetings and changes in the business of the society, in many cases using comments from the past presidents. The valuable and unique diversity of the members is discussed and illustrated, presenting the disciplines and main research areas of the presidents. The number of submitted abstracts and the various categories are tabulated, averaging the number and type over successive periods. A significant increase in the number of abstracts dealing with epidemiology and developmental biology is evident. The society's development is compared to that of a human, and the question was asked by Shephard et al. (2000): Have we reached the maturational stage of old age or senescence, or is the society still maturing gracefully? This question needs further discussion by all the members. By 2010, many positive changes are happening to revitalize the society. During the past 50 years, we have developed the scientific basis to prevent birth defects caused by rubella, alcoholism, and folate deficiency, as well as other prenatal exposures. We are now taking advantage of advances in many fields to begin shaping the Teratology Society of the 21st century. We must now engage in political battles to obtain the resources needed to conduct further research and to implement prevention programs, as well as to provide care and rehabilitation for persons with birth defects.


Evidence that norflurazon affects chloroplast lipid unsaturation in soybean leaves (Glycine max L.).
Norflurazon is a bleaching herbicide known to block carotenoid biosynthesis by inhibiting phytoene desaturase activity. Soybean plants were treated with norflurazon, and we examined the effects on the desaturation of lipid molecular species in leaves using ammonium [1-(14)C] oleate labeling. In monogalactosyldiacylglycerol (MGDG), the main chloroplast lipid, a decrease in 18:3/18:3 molecular species and an increase in its precursors 18:2/18:3 and 18:2/18:2 were observed suggesting that the omega(3) FAD7 desaturase activity in planta was inhibited by norflurazon. The in vitro activity of MGDG synthase was also inhibited by 69%. In contrast, the amount of 18:3/18:3 molecular species of phosphatidylcholine (PC) in the extraplastid compartment increased. The observed increase in in vitro lysoPC-acyltransferase activity and activation of desaturation of [1-(14)C] oleate suggest that extraplastid omega(3)FAD3 desaturase was activated. Analysis of the expression of omega(3) FAD3 and omega(3) FAD7 genes in norflurazon treated plants indicate that omega(3) FAD7 and omega(3) FAD3 desaturases are controlled at the post-transcriptional level.


Cortical network organization reflects clinical response to subthalamic nucleus deep brain stimulation in Parkinson's disease.
The degree of response to subthalamic nucleus deep brain stimulation (STN-DBS) is individual and hardly predictable. We hypothesized that DBS-related changes in cortical network organization are related to the clinical effect. Network analysis based on graph theory was used to evaluate the high-density electroencephalography (HDEEG) recorded during a visual three-stimuli paradigm in 32 Parkinson's disease (PD) patients treated by STN-DBS in stimulation "off" and "on" states. Preprocessed scalp data were reconstructed into the source space and correlated to the behavioral parameters. In the majority of patients (n = 26), STN-DBS did not lead to changes in global network organization in large-scale brain networks. In a subgroup of suboptimal responders (n = 6), identified according to reaction times (RT) and clinical parameters (lower Unified Parkinson's Disease Rating Scale [UPDRS] score improvement after DBS and worse performance in memory tests), decreased global connectivity in the 1-8 Hz frequency range and regional node strength in frontal areas were detected. The important role of the supplementary motor area for the optimal DBS response was demonstrated by the increased node strength and eigenvector centrality in good responders. This response was missing in the suboptimal responders. Cortical topologic architecture is modified by the response to STN-DBS leading to a dysfunction of the large-scale networks in suboptimal responders.


A prospective analysis of islet-cell cytotoxic antibodies in insulin-dependent diabetic children. Transient effects of plasmapheresis.
We determined the effects of plasmapheresis on cytotoxic antibodies to islet cells in 10 children (aged 11-16 yr) with newly diagnosed insulin-dependent diabetes mellitus (IDDM), as well as the plasma levels of antibodies over the next 30 mo and their relation to serum C-peptide concentrations. Complement-dependent, antibody-mediated cytotoxicity (C'AMC) in plasma was measured in a 51Cr release assay using monolayers of the rat islet cell line RINm5F. Cytotoxic antibodies decreased in most IDDM subjects treated by plasmapheresis four times within 2 wk of diagnosis; however, the decreases were small and lasted less than 2-3 days. Thus, both before and after plasmapheresis, 7 of the 10 IDDM children were C'AMC-positive (51Cr release greater than 2 SD above mean for 13 healthy children). After 18-30 mo, only 2 of the original 7 IDDM children with C'AMC-positive plasmas were still positive, and 1 of the original 3 IDDM children without significant cytotoxicity had become positive. Meal-stimulated serum C-peptide responses, measured from diagnosis to 18-30 mo later, did not correlate with C'AMC values. We conclude that (1) plasmapheresis has only transient effects on islet-cytotoxic antibody levels in children with IDDM; (2) these antibodies decrease in most, but not all, subjects over the first 18 mo after diagnosis; and (3) the level of cytotoxic antibodies in IDDM plasma at diagnosis has no predictive effect on residual B-cell function.


High rates of JCV seroconversion in a large international cohort of natalizumab-treated patients.
To retrospectively assess factors associated with John Cunningham virus (JCV) seroconversion in natalizumab-treated patients. Natalizumab is highly effective for the treatment of relapsing-remitting multiple sclerosis (RRMS), but its use is complicated by opportunistic JCV infection. This virus can result in progressive multifocal leukoencephalopathy (PML). Serial assessment of JCV serostatus is mandated during natalizumab treatment. Patients treated with natalizumab for RRMS at six tertiary hospitals in Melbourne, Australia (n = 865) and 11 MS treatment centres in Brazil (n = 136) were assessed for change in JCV serostatus, duration of exposure to natalizumab and prior immunosuppression. Sensitivity analyses examined whether sex, age, tertiary centre, prior immunosuppression or number of JCV tests affected time to seroconversion. From a cohort of 1001 natalizumab-treated patients, durable positive seroconversion was observed in 83 of 345 initially JCV negative patients (24.1%; 7.3% per year). Conversely, 16 of 165 initially JCV positive patients experienced durable negative seroconversion (9.7%; 3.8% per year). Forty patients (3.9%) had fluctuating serostatus. Time-to-event analysis did not identify a relationship between JCV seroconversion and duration of natalizumab exposure. Prior exposure to immunosuppression was not associated with an increased hazard of positive JCV seroconversion. Male sex was associated with increased JCV seroconversion risk [adjusted hazard ratio 2.09 (95% confidence interval 1.17-3.71) p = 0.012]. In this large international cohort of natalizumab-treated patients we observed an annual durable positive seroconversion rate of 7.3%. This rate exceeds that noted in registration and post-marketing studies for natalizumab. This rate also greatly exceeds that predicted by epidemiological studies of JCV seroconversion in healthy populations. Taken together, our findings support emerging evidence that natalizumab causes off-target immune changes that may be trophic for JCV seroconversion. In addition, male sex may be associated with increased positive JCV seroconversion.


Altered expression of caveolin-1 and increased cholesterol in detergent insoluble membrane fractions from liver in mice with Niemann-Pick disease type C.
Niemann-Pick type C (NPC) is an autosomal recessive disease characterized by impaired cholesterol homeostasis due to a defect in the intracellular transport of unesterified cholesterol. While accumulation of lysosomal cholesterol is the most apparent microscopic finding, cholesterol has also been shown to accumulate in the trans-cisternae of the Golgi apparatus. Caveolin-1, a cholesterol-binding protein that cycles between the Golgi apparatus and the plasma membrane, has been hypothesized to participate in cholesterol transport. Using the BALB/c murine model for NPC disease, we found that the expression of caveolin-1 in total liver homogenates from heterozygous and homozygous affected animals was altered. Immunoblot analysis of liver homogenates from heterozygous mice revealed that caveolin-1 is significantly (p < 0.005) elevated, 4.9 fold, compared to normal mice. Total liver homogenates from homozygous affected mice also had a significant (p < 0.05) increase in caveolin-1 expression, 1.6 fold, compared to normal mice. Immunohistochemical staining of liver cross-sections revealed that the increased caveolin-1 was localized to sinusoidal endothelial cells in heterozygous mice. The Triton insoluble floating fraction (TIFF) was isolated using liver from each genotype and analyzed for caveolin-1 expression. Caveolin-1 in the TIFF from heterozygous mice was significantly (p < 0.01) elevated, 1.8 fold, compared to normal and homozygous affected animals; normal and homozygous affected animals, however, were not significantly different from each other. The TIFF isolated from homozygous affected mice revealed a 15 fold increase in unesterified cholesterol compared to the TIFF isolated from heterozygous and normal mice. In summary, these findings demonstrate an altered expression of caveolin-1 in liver from heterozygous and homozygous NPC mice and increased concentration of cholesterol from TIFF in homozygous affected NPC mice. The identification of these alterations in the TIFF suggests involvement of detergent insoluble membrane structures, possibly caveolae and/or detergent insoluble glycosphingolipid-enriched complexes (DIGs), in the cholesterol trafficking defect in this disorder.


Day/Night and Summer/Winter Changes in Serum Total Antioxidant Capacity.
Seasonal and circadian changes are two factors described to affect blood levels of some biological molecules. The Total Antioxidant Capacity (TAC) is one global measure of the antioxidant capacity of a system. There is no agreement about the existence of day/night changes in TAC levels as well as there is no information about seasonal changes in TAC levels. The aims of this research are studying if there are summer/winter changes in TAC concentrations or if TAC concentrations have day/night changes. Ninety-eight healthy subjects took part in the summer study of whom 64 participated in the winter one. Blood was sampled at 09:00, 12:00 and 00:00 h. TAC was measured by the ABTS radical cation technique. Results are expressed in mmol/L of trolox equivalents. The subjects had significantly higher TAC levels in summer than winter at the three-time point studied. Summer 09:00 TAC concentration was significantly higher than the 12:00 and 00:00 h concentrations (1.34±0.26 vs 0.83±0.19, 0.75±0.18). Summer TAC 12:00 h concentrations were significantly higher than the 00:00 h concentrations (0.83±0.19 vs. 0.75±0.18). Winter 09:00 TAC concentrations were significantly higher than the 12:00 and 00:00 h concentrations (1.24±0.16 vs. 0.73±0.10, 0.67±0.13). There were no significant differences between the 12:00 and 00:00 h TAC concentrations. Strong methodological biases may be made if the seasonal and circadian changes in serum TAC concentration are not taken into account when researching in this area.


Transient viral exposure drives functionally-coordinated humoral immune responses in HIV-1 post-treatment controllers.
HIV-1 post-treatment controllers are rare individuals controlling HIV-1 infection for years after antiretroviral therapy interruption. Identification of immune correlates of control in post-treatment controllers could aid in designing effective HIV-1 vaccine and remission strategies. Here, we perform comprehensive immunoprofiling of the humoral response to HIV-1 in long-term post-treatment controllers. Global multivariate analyses combining clinico-virological and humoral immune data reveal distinct profiles in post-treatment controllers experiencing transient viremic episodes off therapy compared to those stably aviremic. Virally-exposed post-treatment controllers display stronger HIV-1 humoral responses, and develop more frequently Env-specific memory B cells and cross-neutralizing antibodies. Both are linked to short viremic exposures, which are also accompanied by an increase in blood atypical memory B cells and activated subsets of circulating follicular helper T cells. Still, most humoral immune variables only correlate with Th2-like circulating follicular helper T cells. Thus, post-treatment controllers form a heterogeneous group with two distinct viral behaviours and associated immune signatures. Post-treatment controllers stably aviremic present "silent" humoral profiles, while those virally-exposed develop functionally robust HIV-specific B-cell and antibody responses, which may participate in controlling infection.


A biomimetic magnetosome: formation of iron oxide within carboxylic acid terminated polymersomes.
Bioinspired macromolecules can aid nucleation and crystallisation of minerals by mirroring processes observed in nature. Specifically, the iron oxide magnetite (Fe3O4) is produced in a dedicated liposome (called a magnetosome) within magnetic bacteria. This process is controlled by a suite of proteins embedded within the liposome membrane. In this study we look to synthetically mimic both the liposome and nucleation proteins embedded within it using preferential orientation polymer design. Amphiphilic block co-polymers self-assemble into vesicles (polymersomes) and have been used to successfully mimic liposomes. Carboxylic acid residue-rich motifs are common place in biomineralisation nucleating proteins and several magnetosome membrane specific (Mms) proteins (namely Mms6) have a specific carboxylic acid motifs that are found to bind both ferrous and ferric iron ions and nucleate the formation of magnetite. Here we use a combination of 2 diblock co-polymers: Both have the hydrophobic 2-hydroxypropyl methacrylate (PHPMA) block with either a poly(ethylene glycol) (PEG) block or a carboxylic acid terminated poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) block. These copolymers ((PEG113-PHPMA400) and (PMPC28-PHPMA400) respectively) self-assemble in situ to form polymersomes, with PEG113-PHPMA400 displaying favourably on the outer surface and PMPC28-PHPMA400 on the inner lumen, exposing numerous acidic iron binding carboxylates on the inner membrane. This is a polymersome mimic of a magnetosome (PMM28) containing interior nucleation sites. The resulting PMM28 were found to be 246 ± 137 nm in size. When the PMM28 were subjected to electroporation (5 pulses at 750 V) in an iron solution, iron ions were transported into the PMM28 polymersome core where magnetic iron-oxide was crystallised to fill the core; mimicking a magnetosome. Furthermore it has been shown that PMM28 magnetopolymersomes (PMM28Fe) exhibit a 6 °C temperature increase during in vitro magnetic hyperthermia yielding an intrinsic loss power (ILP) of 3.7 nHm2 kg-1. Such values are comparable to commercially available nanoparticles, but, offer the added potential for further tuning and functionalisation with respect to drug delivery.


Transcriptional regulation of the gene encoding cholesterol 7 alpha-hydroxylase in the rat.
The cytochrome P450 enzyme, cholesterol 7 alpha-hydroxylase (CYP7A), catalyses the first and rate-limiting step in the conversion of cholesterol to bile acids. Expression of the CYP7A gene is under complex physiological control, encompassing amongst others a feedback down-regulation by bile acids. Using the CYP7A cDNA of the rat as a probe, we isolated a rat genomic clone containing the 5' part of the gene, including approximately 3.6 kb of upstream sequences. Sequence analysis revealed the presence of several putative regulatory elements. Transient expression analyses of transfected primary hepatocytes demonstrated that the major transcription-activating region is located in the proximal 145 nucleotide (nt). Upon addition of taurocholate to the culture, a significant reduction of the transcriptional activity was observed, suggesting the presence of a bile acid-responsive element in the proximal region of the CYP7A promoter. In addition, evidence was obtained for the presence of a thyroxine-responsive site further upstream. After addition of taurocholate, steady-state CYP7A mRNA levels, as judged by Northern analysis of hepatocyte RNA, are eightfold reduced. On the other hand, the transcriptional activity of CYP7A, as shown both in CAT assays and run-on experiments, revealed only a threefold decrease. These experiments suggest that both transcriptional control and regulation of CYP7A mRNA stability play an important part in the feedback regulation of CYP7A activity in the rat.


Matrix metalloproteinase 2 and 9 in esophageal cancer.
To search for the biochemical properties of esophageal carcinoma relevant to its aggressive behavior, we studied metalloproteinases released from surgical specimens of the carcinoma. In an assay with [H-3]-labeled gelatin, esophageal carcinoma tissues showed gelatinolytic activities clearly higher than those of paired normal mucosae. EDTA and TIMP-1 could strongly suppress these activities, suggesting that the activities belong to metalloproteinases. In addition, levels of TIMP-1 expression did not show good correlation with these activities, suggesting that tumor-specific elevation of gelatinolytic activity depended on metalloproteinase per se rather than the suppression of TIMP-1-secretion. By zymographic analysis, two gelatinase bands of 82- and 62-kDa were found specifically in carcinoma tissues, in addition to the other 6 bands detected both in normal and carcinoma tissues. Immunoprecipitation and immunoblotting of gelatinases with anti-MMP-9 or anti-MMP-2 monoclonal antibody, and treatment of the enzymes with APMA showed that these 82- and 62-kDa gelatinases were cleaved products of MMP-9 and MMP-2, respectively. These results imply that enhanced secretion and proteolytic activation of MMP-2 and MMP-9 take place specifically in the esophageal carcinoma tissues. Moreover, the levels of gelatinolytic activity expressed good correlation with the organ metastasis rate of the carcinoma, suggesting that MMPs play an important role in tumor metastasis.


Effects of a phytopreparation from Helleborus niger on immunocompetent cells in vitro.
Extracts of Helleborus species are used as phytopreparations with immunostimulatory properties in Romanian traditional medicine. In Germany, Helleborus niger is used in homeopathy and as an adjuvant therapy in the treatment of tumor patients in anthroposophical medicine. In vitro application of an aqueous extract from Helleborus niger resulted in a slight induction of sister chromatid exchanges (SCE) in cultured peripheral blood mononuclear cells (PBMC) from healthy individuals, an effect associated with a slight increase of the [3H]thymidine uptake in the DNA of isolated lymphocytes. Since the cytokines interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha were reported to increase the number of SCE, we measured the concentrations of these cytokines in the supernatants of cultured PBMC treated with the plant extract. Here, no significant changes were observed as compared with the controls, but a trend to higher supernatant concentrations of TNF-alpha in six out of ten individuals was noted. Compared with lymphocytes treated with the alkylating substance, cyclophosphamide, the increase of the SCE levels induced by the plant extract is weak. The relevance of this DNA destabilizing property remains to be clarified.


The FXG: a presynaptic fragile X granule expressed in a subset of developing brain circuits.
The loss of Fragile X mental retardation protein (FMRP) causes Fragile X syndrome, the most common inherited mental retardation and single gene cause of autism. Although postsynaptic functions for FMRP are well established, potential roles at the presynaptic apparatus remain largely unexplored. Here, we characterize the expression of FMRP and its homologs, FXR1P and FXR2P, in the developing, mature and regenerating rodent nervous system, with a focus on presynaptic expression. As expected, FMRP is expressed in the somatodendritic domain in virtually all neurons. However, FMRP is also localized in discrete granules (Fragile X granules; FXGs) in a subset of brain regions including frontal cortex, hippocampal area CA3 and olfactory bulb glomeruli. Immunoelectron microscopy shows that FMRP is localized at presynaptic terminals and in axons within these FXG-rich regions. With the exception of the olfactory bulb, FXGs are prominent only in the developing brain. Experiments in regenerating olfactory circuits indicate that peak FXG expression occurs 2-4 weeks after neurogenesis, a period that correlates with synapse formation and refinement. Virtually all FXGs contain FXR2P, while region-selective subsets harbor FMRP and/or FXR1P. Genetic studies show that FXR2P is essential for FXG expression, while FMRP regulates FXG number and developmental profile. These findings suggest that Fragile X proteins play a distinct, presynaptic role during discrete developmental epochs in defined circuits of the mammalian CNS. We propose that the neurological defects in Fragile X syndrome, including the autistic features, could be due in part to the loss of FMRP function in presynaptic compartments.


Investigation of glycofullerene dynamics by NMR spectroscopy.
Glycofullerenes, in which carbohydrate molecules are attached via a linker to a [60]fullerene core, facilitate spherical presentation of glyco-based epitopes. We herein investigate the dynamics of two glycofullerenes, having 12 and 36 mannose residues at their periphery, by NMR translational diffusion and quantitative (13)C relaxation studies employing a model-free approach for their interpretation. The sugar residues are shown to be highly flexible entities with S(2) < 0.2 in both compounds. Notably, the larger glycofullerene with longer linkers shows faster internal dynamics and higher flexibility than its smaller counterpart. The dynamics and flexibility as well as the slower translational diffusion of the larger glycofullerene, thereby favoring rebinding to a receptor, may together with its spatial extension explain why it is better than the smaller one at blocking the DC-SIGN receptor and inhibiting the infection by pseudotyped Ebola virus particles.


Ectopic expression of cadherin 8 is sufficient to cause cyst formation in a novel 3D collagen matrix renal tubule culture.
While a variety of genetic mutations have been shown to be associated with renal cyst formation, mechanisms of renal cyst formation are largely unknown. In prior communications we described alterations in E-cadherin assembly in cultured cystic epithelial cells (Charron AJ, Nakamura S, Bacallao R, Wandinger-Ness A. J Cell Biol 149: 111-124, 2000). Using the same cell line we assayed cadherin expression by RT-PCR using primer pairs that anneal to highly conserved sequences of cadherin genes but flank informative regions of cadherins. Using this approach we found that autosomal dominant polycystic kidney disease (ADPKD) cells express cadherin 8, a neuronal cadherin with limited expression in the kidney. Immunohistochemistry confirmed cadherin 8 expression in cystic epithelia. To test the functional significance of cadherin 8 expression in renal epithelial cells, we adapted a three-dimensional collagen culture method in which HK-2 cells form tubule structures and microinjected adenovirus into the matrix space surrounding tubule structures. Adenovirus expressing cadherin 8 under the control of a tet promoter caused cyst structures to grow out of the tubules when coinjected with adenovirus expressing a tet transactivator. Microinjection of single adenovirus expressing either tet transactivator or cadherin 8 failed to cause cyst formation. When doxycycline was added to the culture, following coinjection of adenovirus, there was a dose-response reduction in cadherin 8 expression and cyst formation. Similarly, HK-2 cells transfected with Flag-tagged cadherin 8 form cysts in addition to tubular structures. HK-2 cells transfected with Flag-tagged N-cadherin do not form cysts. These data suggest that ectopic expression of cadherin 8 in renal epithelial cells is sufficient to cause the morphogenic pattern of cyst formation.


Decision making among Veterans with incidental pulmonary nodules: a qualitative analysis.
Among patients undergoing lung cancer evaluation for newly diagnosed, incidental pulmonary nodules, it is important to evaluate the shared power and responsibility domain of patient-centered communication. We explored Veterans' perceptions of decision making with regards to an incidentally-detected pulmonary nodule. We conducted semi-structured, qualitative interviews of 19 Veterans from one medical center with incidentally-detected pulmonary nodules that were judged as having a low risk for malignancy. We used qualitative description for the analysis, focusing on patients' perceptions of shared decision making with their primary care provider (PCP). Interviews were conducted in 2011 and 2012. Patients almost always played a passive role in deciding how and when to evaluate their pulmonary nodule for the possibility of malignancy. Some patients felt comfortable with this role, expressing trust that their clinician would provide the appropriate care. Other patients were not satisfied with how these decisions were made with some expressing concern that no decisions had actually occurred. Regardless of how satisfied they were with the decision, patients did not report discussing how they liked to make decisions with their PCP. Veterans in our study did not engage in shared decision making with their clinician. Some were satisfied with this approach although many would have preferred a shared approach. In order to reduce patient distress and improve satisfaction, clinicians may want to consider adopting a shared approach when making decisions about pulmonary nodule evaluation.


Expression of PGP9.5 in ductal cells of the rat pancreas during development and regeneration: can it be a marker for pancreatic progenitor cells?
The expression of protein gene product 9.5 (PGP9.5), a known neuron marker, was immunohistochemically investigated in rat pancreas. In fetal pancreas, a cluster of cells expressed PGP9.5 among the initial epithelial buds at embryonic day 11.5 (E 11.5). At E 13.5, PGP9.5 appeared among elongated and branching epithelial cells as well as along nerve fibers in the mesenchyme. On E 17.5, tubular cells became ductal cells with lumen, which strongly expressed PGP9.5. In newborn rats, ductal cells of the common bile duct (CBD) to the centroacinar cells and islet cells expressed PGP9.5. Ten days after birth, the number of the ductal cells expressing PGP9.5 was reduced, and PGP9.5-negative cells appeared in half of the duct cells. On day 21, all centroacinar cells and intercalated ductal cells became PGP9.5-negative, but some CBD and interlobular ductal cells remained positive for PGP9.5. On day 28 and thereafter, PGP9.5 was no longer detected. In a pancreatic duct ligation model, acinar cells changed to cells with duct-like structure after duct ligation. These cells strongly expressed PGP9.5 on the fifth day after duct ligation. Three to four weeks after ligation, the cells with duct-like structure changed to acinar cells, islets of Langerhans and ductal cells, but the ductal cells were PGP9.5-negative at this point. These results suggested that PGP9.5 is expressed in ductal cells that possess a potential for differentiation to pancreatic endocrine cells, and therefore can serve as a marker for the progenitor of pancreatic endocrine cells.


Measurement of plasma phenytoin by EMIT in the Monarch centrifugal analyzer: studies on the elimination of within-rotor drift.
We investigated the measurement of phenytoin in plasma by the EMIT method, in the Monarch centrifugal analyzer. When we used the standard protocol supplied by Instrumentation Laboratory, significant drift was observed across a full rotor loaded with 31 replicates of a single specimen. Although the cause remains obscure, the drift was eliminated by using a load-spin-reload-spin procedure. This makes it possible to analyze large batches of samples without excessive use of standards and reagents.


A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue-induced cocaine craving following prolonged abstinence.
Following exposure to drugs of abuse, long-term neuroadaptations underlie persistent risk to relapse. Endocannabinoid signaling has been associated with drug-induced neuroadaptations, but the role of lipases that mediate endocannabinoid biosynthesis and metabolism in regulating relapse behaviors following prolonged periods of drug abstinence has not been examined. Here, we investigated how pharmacological manipulation of lipases involved in regulating the expression of the endocannabinoid 2-AG in the nucleus accumbens (NAc) influence cocaine relapse via discrete neuroadaptations. At prolonged abstinence (30 days) from cocaine self-administration, there is an increase in the NAc levels of diacylglycerol lipase (DAGL), the enzyme responsible for the synthesis of the endocannabinoid 2-AG, along with decreased levels of monoacylglycerol lipase (MAGL), which hydrolyzes 2-AG. Since endocannabinoid-mediated behavioral plasticity involves phosphatase dysregulation, we examined the phosphatase calcineurin after 30 days of abstinence and found decreased expression in the NAc, which we demonstrate is regulated through the transcription factor EGR1. Intra-NAc pharmacological manipulation of DAGL and MAGL with inhibitors DO-34 and URB-602, respectively, bidirectionally regulated cue-induced cocaine seeking and altered the phosphostatus of translational initiation factor, eIF2α. Finally, we found that cocaine seeking 30 days after abstinence leads to decreased phosphorylation of eIF2α and reduced expression of its downstream target NPAS4, a protein involved in experience-dependent neuronal plasticity. Together, our findings demonstrate that lipases that regulate 2-AG expression influence transcriptional and translational changes in the NAc related to drug relapse vulnerability.


Synaptic Components, Function and Modulation Characterized by GCaMP6f Ca2+ Imaging in Mouse Cholinergic Myenteric Ganglion Neurons.
The peristaltic contraction and relaxation of intestinal circular and longitudinal smooth muscles is controlled by synaptic circuit elements that impinge upon phenotypically diverse neurons in the myenteric plexus. While electrophysiological studies provide useful information concerning the properties of such synaptic circuits, they typically involve tissue disruption and do not correlate circuit activity with biochemically defined neuronal phenotypes. To overcome these limitations, mice were engineered to express the sensitive, fast Ca2+ indicator GCaMP6f selectively in neurons that express the acetylcholine (ACh) biosynthetic enzyme choline acetyltransfarse (ChAT) thereby allowing rapid activity-driven changes in Ca2+ fluorescence to be observed without disrupting intrinsic connections, solely in cholinergic myenteric ganglion (MG) neurons. Experiments with selective receptor agonists and antagonists reveal that most mouse colonic cholinergic (i.e., GCaMP6f+/ChAT+) MG neurons express nicotinic ACh receptors (nAChRs), particularly the ganglionic subtype containing α3 and β4 subunits, and most express ionotropic serotonin receptors (5-HT3Rs). Cholinergic MG neurons also display small, spontaneous Ca2+ transients occurring at ≈ 0.2 Hz. Experiments with inhibitors of Na+ channel dependent impulses, presynaptic Ca2+ channels and postsynaptic receptor function reveal that the Ca2+ transients arise from impulse-driven presynaptic activity and subsequent activation of postsynaptic nAChRs or 5-HT3Rs. Electrical stimulation of axonal connectives to MG evoked Ca2+ responses in the neurons that similarly depended on nAChRs or/and 5-HT3Rs. Responses to single connective shocks had peak amplitudes and rise and decay times that were indistinguishable from the spontaneous Ca2+ transients and the largest fraction had brief synaptic delays consistent with activation by monosynaptic inputs. These results indicate that the spontaneous Ca2+ transients and stimulus evoked Ca2+ responses in MG neurons originate in circuits involving fast chemical synaptic transmission mediated by nAChRs or/and 5-HT3Rs. Experiments with an α7-nAChR agonist and antagonist, and with pituitary adenylate cyclase activating polypeptide (PACAP) reveal that the same synaptic circuits display extensive capacity for presynaptic modulation. Our use of non-invasive GCaMP6f/ChAT Ca2+ imaging in colon segments with intrinsic connections preserved, reveals an abundance of direct and modulatory synaptic influences on cholinergic MG neurons.


Characterisation of a new isolate of Mycobacterium shimoidei from Finland.
This report describes the first isolation of Mycobacterium shimoidei in Finland from a sputum specimen obtained from an elderly female patient. M. shimoidei, a potential lung pathogen, is difficult to identify by routine methods and only a few cases have been reported. The present study demonstrated that M. shimoidei has a characteristic pattern for fatty acids and alcohols in gas liquid chromatography. This chromatogram and the pattern of mycolic acids on thin-layer chromatography allow it to be distinguished routinely. The unique sequence of the 16S rRNA gene and the 16S-23S rDNA spacer region allows identification by molecular methods.


Comparative evaluation of roughness of titanium surfaces treated by different hygiene instruments.
The use of appropriate instruments to clean surfaces with minimal change, is critical for the successful maintenance of a dental implant. However, there is no consensus about the type and methodology for such instruments. The aim of this study was to characterize changes in the roughness of titanium surfaces treated by various scaling instruments. Thirty-seven identical disks (5 mm in diameter) were investigated in this study. The specimens were divided into eight groups according to the types of instrumentation and the angle of application. Ultrasonic scaling systems were applied on a titanium disk to simulate standard clinical conditions. The equipment included a piezoelectric ultrasonic scaler with a newly developed metallic tip (NS group), a piezoelectric ultrasonic scaler with a conventional tip (CS group), a piezoelectric root planer ultrasonic scaler with a conventional tip (PR group), and a plastic hand curette (PH group). In addition, the sites treated using piezoelectric ultrasonic scaler systems were divided two sub-groups: 15 and 45 degrees. The treated titanium surfaces were observed by scanning electron microscopy (SEM), and the average surface roughness (Ra) and mean roughness profile depth (Rz) were measured with a profilometer. SEM no significant changes in the titanium surfaces in the NS group, regardless of the angle of application. The PH group also showed no marked changes to the titanium surface, although some smoothening was observed. All CS and PR sites lost their original texture and showed irregular surfaces in SEM analysis. The profilometer analysis demonstrated that the roughness values (Ra and Rz) of the titanium surfaces increased in all, except the PH and NS groups, which showed roughness decreases relative to the untreated control group. The Ra value differed significantly between the NS and PR groups (P<0.05). The results of this study indicated that changes in or damage to titanium surfaces might be more affected by the hardness of the scaler tip than by the application method. Within the limitations of this study, the newly developed metallic scaler tip might be especially suitable for peri-implant surface decontamination, due to its limited effects on the titanium surface.


[Monosaccharide composition of some Mollicutes].
When studying a small group of mollicutes which interact in different way with the host organism (Mycoplasma fermentans PG18--is considered a commensal of the human urogenital tract, and sometimes manifests as AIDS cofactor, Acholeplasma laidlawii PG8 is saprophytic but it is connected with various pathologies in human organism, A. laidlawii var. granulum 118--agent of the yellow of cereals--palegreen dwarfness) the author has found the carbohydrate composition of their cell surface. Glycocalix of all three representatives proved to be rather various. Biochemical investigation methods were used to establish the presence of galactosamine, glucosamine, minor quantity of rhamnose, ribose, arabinose, xylose, mannose as well as considerable share of fucose, galactose, glucose. Qualitative and quantitative content of monosaccharide composition of the glycocalix of certain species of mollicutes which have different ecological niches is studied in the work and the role of some sugars in performing certain important functions is discussed.


The Role and Response of Palliative Care and Hospice Services in Epidemics and Pandemics: A Rapid Review to Inform Practice During the COVID-19 Pandemic.
Cases of coronavirus disease 2019 (COVID-19) are escalating rapidly across the globe, with the mortality risk being especially high among those with existing illness and multimorbidity. This study aimed to synthesize evidence for the role and response of palliative care and hospice teams to viral epidemics/pandemics and inform the COVID-19 pandemic response. We conducted a rapid systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in five databases. Of 3094 articles identified, 10 were included in this narrative synthesis. Included studies were from West Africa, Taiwan, Hong Kong, Singapore, the U.S., and Italy. All had an observational design. Findings were synthesized using a previously proposed framework according to systems (policies, training and protocols, communication and coordination, and data), staff (deployment, skill mix, and resilience), space (community provision and use of technology), and stuff (medicines and equipment as well as personal protective equipment). We conclude that hospice and palliative services have an essential role in the response to COVID-19 by responding rapidly and flexibly; ensuring protocols for symptom management are available, and training nonspecialists in their use; being involved in triage; considering shifting resources into the community; considering redeploying volunteers to provide psychosocial and bereavement care; facilitating camaraderie among staff and adopting measures to deal with stress; using technology to communicate with patients and carers; and adopting standardized data collection systems to inform operational changes and improve care.


Heteromeric interactions among nucleoid-associated bacterial proteins: localization of StpA-stabilizing regions in H-NS of Escherichia coli.
The nucleoid-associated proteins H-NS and StpA in Escherichia coli bind DNA as oligomers and are implicated in gene regulatory systems. There is evidence for both homomeric and heteromeric H-NS-StpA complexes. The two proteins show differential turnover, and StpA was previously found to be subject to protease-mediated degradation by the Lon protease. We investigated which regions of the H-NS protein are able to prevent degradation of StpA. A set of truncated H-NS derivatives was tested for their ability to mediate StpA stability and to form heteromers in vitro. The data indicate that H-NS interacts with StpA at two regions and that the presence of at least one of the H-NS regions is necessary for StpA stability. Our results also suggest that a proteolytically stable form of StpA, StpA(F21C), forms dimers, whereas wild-type StpA in the absence of H-NS predominantly forms tetramers or oligomers, which are more susceptible to proteolysis.


Methodologic issues in the measurement of cytokines to elucidate the biological basis for cancer symptoms.
Multiple concurrent symptoms are highly prevalent in patients with cancer. However, little is known about the relationships among these symptoms and their underlying mechanisms. A number of cytokines that are involved in the development of sickness behavior are hypothesized to be a mechanism for symptom clusters. Measurement of these cytokines would provide valuable information that could be used to elucidate mechanisms underlying the development of symptom clusters and the identification of potential targets for intervention studies. In this article, the authors explore several issues that warrant careful consideration when designing a research study involving the use of a cytokine as a biomarker in symptom cluster research. These issues include which molecules to measure, which specimens to collect, the timing of specimen collection and processing, and which technologies to use to measure the biomarker and the sensitivity and specificity of the assay system. The article begins with a brief discussion of cytokines and sickness behavior and the role of the cytokines in cancer-related symptoms.


Multiple antibiotic-resistant bacteria on fluted pumpkin leaves, a herb of therapeutic value.
Fluted pumpkin (Telfairia occidentalis) is a minimally-processed green leafy vegetable traditionally used for its antianaemic properties in the form of leaf juice without a heating or inactivation step before consumption. The aim of the study was to assess the presence of surface microbiota on T. occidentalis leaves and also to determine the antimicrobial susceptibility of isolated organisms. Bacterial contaminants on 50 samples of T. occidentalis leaves were isolated and characterized using standard biochemical methods and the antimicrobial susceptibility of isolated organisms was determined using the antibiotic disc diffusion assay. The results obtained show that the leaves of T. occidentalis is contaminated with organisms which included Enterobacter agglomerans (25.9%), Proteus vulgaris (24.9%), Klebsiella spp. (2.6%), and Serratia liquefaciens (2.1%). Other bacterial isolates recovered in order of frequency included: Staphylococcus spp. (33.7%), Bacillus spp. (8.3%), and Pseudomonas fluorescens (2.6%). Of the 193 bacterial isolates from the leaves of T. occidentalis samples tested for antimicrobial resistance, all (100%) were found to be resistant to ampicillin, cloxacillin, augmentin, erythromycin, and tetracycline while 96% of the isolates were resistant to cephalothin. Resistance to trimethoprim (93%) and gentamicin (83%) was also observed. Approximately, 22% of the isolates were resistant to ciprofloxacin; however, only 11 (5.8%) were resistant to ofloxacin. Thus, uncooked T. occidentalis is a potential source of highly-resistant epiphytic bacteria which could be opportunistic pathogens in consumers.


Personalized prognosis and diagnosis of type 2 diabetes--vision or fiction?
Typical civilization diseases, such as type 2 diabetes, share several features: their worldwide frequency, the complexity of the underlying pathogenic mechanisms, heterogeneity in the phenotypes and their multifactorial nature due to a wide variety of possible combinations of disease susceptibility or protective genes in different tissues and negative or positive environmental factors. This is in sharp contrast to classical inherited diseases, such as Huntington's chorea, which are often caused by complete loss- or gain-of-function mutations in a single gene. The causative polymorphisms of susceptibility genes, however, are characterized by relatively subtle alterations in the function of the corresponding gene products, i.e. low penetrance and effect size, which do not support the pathogenesis per se, and by their high frequency; these two characteristics result in high expenditures for their identification and a rather low predictive value. In the future, the reliable and early diagnosis of common diseases will thus depend on the determination of all (or as many as possible) polymorphisms of each susceptibility gene together with the corresponding gene products and the metabolites emerging thereof for each individual. Great hopes are currently associated with systems biology to cover these demands in time (i.e. along the pathogenesis) and space (i.e. in all relevant tissues).


Things we can do now that we could not do before: Developing and using a cross-scalar, state-wide database to support geomorphologically-informed river management.
A fundamental premise of river management is that practitioners understand the resource they are working with. In river management this requires that baseline information is available on the structure, function, health and trajectory of rivers. Such information provides the basis to contextualise, to plan, to be proactive, to prioritise, to set visions, to set goals and to undertake objective, pragmatic, transparent and evidence-based decision making. In this paper we present the State-wide NSW River Styles database, the largest and most comprehensive dataset of geomorphic river type, condition and recovery potential available in Australia. The database is an Open Access product covering over 216,600 km of stream length in an area of 802,000 km2. The availability of the database presents unprecedented opportunities to systematically consider river management issues at local, catchment, regional and state-wide scales, and appropriately contextualise applications in relation to programs at other scales (e.g. internationally)-something that cannot be achieved independent from, or without, such a database. We present summary findings from the database and demonstrate through use of examples how the database has been used in geomorphologically-informed river management. We also provide a cautionary note on the limitations of the database and expert advice on lessons learnt during its development to aid others who are undertaking similar analyses.


[Extent of platelet aggregation inhibition and clinical events: new evidence with prasugrel].
Clopidogrel in combination with aspirin is the recommended standard of care for reducing the occurrence of cardiovascular events in patients presenting with acute coronary syndromes; these protective effects of clopidogrel have been shown both in patients undergoing percutaneous coronary intervention (PCI) and in those treated with medical therapy alone. However, significant shortcomings still exist, including a delayed onset of action in platelet inhibition, individual response variability (with some patients being frankly hyporesponsive), and a prolonged time to recovery of platelet function following cessation of treatment. Among these, clopidogrel hyporesponsiveness seems to be particularly important, as a growing body of evidence suggests that residual platelet reactivity on clopidogrel is associated with a significant increase in the risk of developing adverse clinical events. Prasugrel is a novel, third-generation oral thienopyridine that is a specific, irreversible antagonist of the platelet adenosine 5'-diphosphate P2Y12 receptor. Prasugrel has more potent antiplatelet activity, faster onset of action, and less interpatient variability as compared to clopidogrel. These pharmacodynamic properties led prasugrel to be more effective in preventing ischemic events in patients with acute coronary syndromes undergoing PCI in the setting of the recent TRITON-TIMI 38 study. However, the greater protective effects toward ischemic events were partially counterbalanced by an increased risk of bleeding, particularly in patients with history of transient ischemic attack/stroke, in those with body weight <60 kg and in those older than 74 years. A favorable net clinical benefit of prasugrel compared with clopidogrel has been shown.